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REVIEW ARTICLE OPEN

Sustained effects of single doses of classical psychedelics in

humans
1✉
Gitte M. Knudsen

© The Author(s) 2022

The serotonergic classical psychedelics include compounds that primarily activate the brain’s serotonin 2 A receptor (5-HT2AR),
such as LSD, psilocybin, and DMT (ayahuasca). The acute effects of these compounds are well-known as are their ability to increase
the emotional state both in healthy people and in those with neuropsychiatric disorders. In particular psilocybin, the psychoactive
constituent in “magic mushrooms”, has shown great potential for treatment of anxiety and depression. A unique and compelling
feature of psychedelics is that intake of just a single psychedelic dose is associated with long-lasting effects. This includes effects on
personality, e.g., higher openness, and amelioration of depressive symptoms. This review focuses on these stunning effects and
summarizes our current knowledge on which behavioral, biochemical, neuroimaging, and electrophysiological data support that
the intriguing effects of psychedelics on the human brain and mind are based on neural plasticity. The review also points to so far
understudied areas and suggests research questions to be addressed in future studies which potentially can help to understand the
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intriguing long-term effects after intake of a single (or a few) psychedelic doses.

Neuropsychopharmacology (2023) 48:145–150; https://doi.org/10.1038/s41386-022-01361-x

INTRODUCTION lasting effects on Openness after a single dose of psilocybin in

A unique and compelling feature of classical psychedelics is that
intake of just a single psychedelic dose is associated with long-
lasting (i.e., weeks-years) effects in humans. These include effects
on behaviors, attitudes, values, and personality, i.e., elements of a
human’s individuality that normally are regarded as relatively
stable throughout adulthood. Moreover, these effects are
apparent not only in healthy individuals but also in patients
diagnosed with various neuropsychiatric disorders, most notably
depression and anxiety, who may experience amelioration of their
depressive and anxious symptoms. The evidence for the effects is
reviewed below; here, acute effects are defined as those present
while the drug is still present in plasma and long-term effects are
those observed after 1 week, or later.
In a ten-year follow-up study including 247 individuals, intake of
LSD, whether with or without a psychotherapeutic setting,
resulted in positive personality changes but only in the 23%
who subsequently used LSD again [1]. A smaller but controlled
study of 16 healthy individuals who were followed-up after 12-
months found no changes in personality [2]. In another better
controlled longitudinal study of 52 psychedelic-naïve healthy
participants who underwent up to four session involving varying
doses of psilocybin, the personality trait Openness (as measured
with NEO-PI) was increased 1–2 months and 14 months after the
intervention [3]. In a subset of this cohort, individuals also
reported on externally validated positive changes in attitudes,
mood, and behavior 14 months later, with the ascending dose
sequence showing greater positive effects [4] and this has since
been replicated in several studies [5], including a large web-based
study involving different psychedelics [6]. The observation of long-
healthy individuals has subsequently been replicated in, e.g., [7].
Compared with placebo, psilocybin also enhances mindfulness
and improves psychosocial functioning at 3-4-month follow-up [8].
Data on personality and well-being from classical psychedelics
other than psilocybin are more limited. In a placebo-controlled
study in 20 healthy volunteers, Openness was significantly
increased 2 weeks post LSD [9] whereas a similar trial in 16
healthy individuals did not find significant changes in Openness
one and 12 months after LSD [2]. On the other hand, the latter
study did reveal higher positive attitudes about life and/or self,
positive mood changes, social effects, and behavioral changes,
and well-being/life satisfaction both at 1 and 12 months [2].
Ayahuasca (consisting of N,N-Dimethyltryptamine (DMT) and a
monoamine oxidase inhibitor) also seems to produce less
consistent effects on personality; Openness 3 weeks post-drug
intake increased in only one of two trials [10], but relative to
baseline, it enhanced emotional and cognitive processes, lasting
up to 4 weeks after the experience [11, 12]. It should be
mentioned that some of these studies were observational and far
from all placebo controlled. The field of psychedelic research is
particularly prone to suffer from inability to appropriate blinding
and by study participants often being biased towards use of
psychedelics. The psychological effects of psychedelics in healthy
controls and patient groups were recently assessed in a systematic
review and meta-analysis [13] which also identified the need for
careful, large-scale, placebo-controlled randomized trials.
Given that moderate-high doses of psilocybin are required to
induce lasting changes in personality and mood, does the content
of the experience then matter? Such observations would be

Neurobiology Research Unit, Rigshospitalet and Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark. ✉email: gmk@nru.dk
1

Received: 4 April 2022 Revised: 19 May 2022 Accepted: 1 June 2022

Published online: 21 June 2022
 G.M. Knudsen
146
important to understand whether the psychedelic experience is a
prerequisite for long-term effects. In a seminal paper, it was noted
that participants who had so-called mystical experiences during
their psilocybin session, Openness remained significantly higher
than baseline more than one year after the session and the
change was correlated to the intensity of the mystical experience
[3]. There is also additional evidence that the strength of mystical
experience may correlate with therapeutic effects in smokers [14]
and with diminished anxiety and depression in terminal cancer
patients [15–17]. Common dimensions in mystical experiences
include the experience of profound unity with all that exists, a felt
sense of sacredness, a sense of the experience of truth and reality
at a fundamental level, deeply felt positive mood, transcendence
of time and space, and difficulty explaining the experience in
words, this has been assessed with different versions of the
Mystical Experience Questionnaire (MEQ), developed and vali-
dated based on psilocybin sessions [18]. Interestingly, we have
observed in our studies that those individuals who have a
psilocybin-elicited mystical experience (roughly half of them) also
tend to have a mystical experience when sessions are repeated
later (unpublished observation). These as well as other observa-
tions have fostered a functional neural model of mystical
experience [19].
A separate question is if these psychedelics-associated effects
on personality and mood in healthy individuals are mechan-
istically related to the therapeutic effects reported in patients with
depression or anxiety. There is some data in support of that view:
In 20 patients with moderate or severe, unipolar, treatment-
resistant depression (TRD), psilocybin (10 and 25 mg, one week
apart) lead to an increase in Openness and an increase in
Extraversion at 3-month follow-up [20]; this observation should be
seen in the light of observed increase in Neuroticism and decrease
in Extraversion found in patients with seasonal affective disorder
when comparing their depressed state to their symptom-free
states [21]. The psilocybin-associated increase in Openness might
thus constitute an effect more specific to psychedelic therapy.
Cognitive flexibility, broadly defined as the ability to adaptively
switch between different cognitive operations in response to
changing demands, is a core characteristic of Openness [22] and is
often impaired in major depressive disorder (MDD). It has indeed
been found that patients with MDD who are treated with
psilocybin have increased cognitive flexibility for at least 4 weeks
after [23].
Psychedelic therapy for psychiatric disorders is also unique in
that the effects are instantaneous after the first session and to the
extent that there are follow-up data beyond 6–12 months, it does
not (always) require additional sessions to maintain the effect
beyond that observation period. In a recent review of 10
independent psychedelic-assisted therapy trials (7 with psilocybin,
2 with ayahuasca, and one with LSD), including patients with
anxiety, depression, obsessive-compulsive or substance abuse
disorders, the therapeutic effects appeared to be long-lasting
(3 weeks - 6 months) after only 1 to 3 treatment session(s) [24].
New studies are continuously added, e.g., a recent study where
ayahuasca was given to patients with depression shows beneficial
effects, lasting for more than a year [25].
How do these personality and mood effects of psychedelics in
humans then back-translate to animals? That could be the topic of
whole other review, but it suffices here to say that the drug-
induced head twitch response (HTR), commonly taken as a proxy
for acute psychedelic effects in animal, does require comparably
larger psychedelic doses in animals and generally, most animal
studies do involve larger drug doses. Since psychedelic effects of
psilocybin in humans correlate with 5-HT2AR occupancy and
plasma psilocin levels [26] we have previously suggested that in
order to compare animal behavior to human psychedelic effects
[27], one should use doses that also generate a 5-HT2AR
occupancy of 40–70% in animals.
The neurobiological mechanism behind the stunning psycho-
logical long-term action of classical psychedelics has recently
become a key question, that mostly has been investigated in
animal studies, as reviewed in, e.g., [28]. The findings point to
psychedelics inducing molecular and cellular adaptations related
to neuroplasticity and these are suggested to occur in parallel to
and potentially underly the clinical effects of psychedelics. A
relevant question is if epigenetic-driven changes in synaptic
plasticity are the mechanistic substrate of psychedelic’s long-
lasting actions in humans; data on this topic is also starting to
emerge [29].
The remaining part of this review will address how the effects of
psychedelics on the neuroplasticity measured observed in animal
studies can be tested in humans. Although the methodologies
that can be applied to study molecular, structural or functional
neuroplasticity in humans are more limited, the evidence for
neuroplastic effects taking place and potentially explaining some
of the beneficial effects in humans are summarized below.
BLOOD MEASURES OF NEUROPLASTICITY
Molecular changes as part of neuronal plasticity (signaling
pathways, gene expression, and protein synthesis) are difficult to
assess in vivo in the human brain but Brain Derived Neurotrophic
Factor (BDNF) or other neurotrophic factors can be measured in
serum or whole blood [30]. Plasma and cerebrospinal fluid BDNF
in humans are, on the other hand, considered too low to be
reliably determined and an association between blood and brain
BDNF remains to be shown in humans. In support of using serum
or whole blood BDNF as a proxy for brain BDNF levels, however, is
the evidence that across species, peripheral measures of BDNF
reflects the brain tissue content [31].
Serum or blood BDNF is lower in patients with MDD [32] and
most studies show that treatment for several weeks with selective
serotonin reuptake inhibitors (SSRIs) increases serum BDNF [33–
35], in line with the hypothesis of SSRI’s also acting through
neuroplastic changes. The temporal BDNF response to classical
psychedelics is less well studied. Two studies investigated the
acute effects of LSD on BDNF: When low doses of LSD (5, 10, and
20 μg) were given to healthy volunteers, plasma BDNF increased
at 4 h (5 μg) and 6 h (5 and 20 μg), compared to placebo [36].
When higher doses of LSD (25, 50, 100, and 200 µg) were given,
plasma BDNF levels were increased up to 12 h after and only at
the 200 µg LSD dose [37]. Both these studies did, however, analyze
BDNF in plasma samples which as mentioned above is considered
suboptimal since the low levels makes it difficult to measure
it accurately and even a minor leakage from the thrombocytes can
confound the BDNF measurement. A single dose of ayahuasca
also increased serum BDNF levels 48 h after in the active
compared to the placebo group; in both healthy controls and
patients with TRD [38].
In summary, although there is some data to support that
peripheral BDNF is increased up to 12 h after LSD and 48 h after
ayahuasca, its eventual relevance for emergence of long-term
effects on personality and mood is unclear. It is also unknown how
long after the psychedelic drug intervention BDNF remains
elevated.
MOLECULAR, STRUCTURAL AND FUNCTIONAL
NEUROPLASTICITY: NEUROIMAGING STUDIES
Positron emission tomography (PET)
The classical psychedelics LSD, psilocin and DMT (the psychedelic
component of ayahuasca) also target other receptors than
5-HT2AR [39]. There is little doubt, however, that stimulation of
the neocortical 5-HT2AR is a requirement for the psychedelic
experience to occur. Blocking 5-HT2A/5-HT2C receptors with the
5-HT2AR antagonist ketanserin abolishes virtually all of the
Neuropsychopharmacology (2023) 48:145 – 150

subjective effects of subsequently given psilocybin, LSD, and DMT
in humans [40] and there is a tight correlation between plasma
psilocin, cerebral 5-HT2AR occupancy as measured with PET, and
the perceived intensity of the psychedelic experience [26]. This
means that measuring individuals’ plasma psilocin levels can give
a good estimate of the brain 5-HT2AR occupancy which facilitates
comparisons across individuals [41].
As mentioned above, increased Openness is one of the key
features of long-term effects. Interestingly, neocortex 5-HT2AR
binding as measured with PET has been found to be negatively
associated with both the peak plateau duration of the psychedelic
experience and with the mystical experience total score [42]
meaning that individual differences in baseline cerebral 5-HT2AR
may make individuals more prone to the positive/therapeutic
effects of psychedelics. In 10 psychedelic-preferring recreational
users, 14 MDMA-preferring users and 21 non-using controls,
Openness scores differed between the three groups; psychedelic-
preferring recreational users showing higher Openness compared
with both MDMA-preferring users and controls [43]. Openness
scores were positively associated with lifetime number of
psychedelic exposures, and among all MDMA-preferring user/
psychedelic-preferring recreational user individuals, frontal sero-
tonin transporter - but not frontal 5-HT2AR binding - was
positively associated with Openness [43]. Regular use of psyche-
delics could also matter: Regular users of classical psychedelics
have lower neocortex 5-HT2AR than non-users [44] but since these
observations are cross-sectional, it is difficult to determine if
cerebral 5-HT2AR is a trait or state marker. In other words, are the
psychedelic recreational users more prone to use psychedelics
because of their lower 5-HT2AR, or does the 5-HT2AR down-
regulate in response to use of psychedelics? There is some data to
support the latter: A single psilocybin dose leads to increased
mindfulness as measured 3 months later, preceded by a
proportional relative decrease in neocortical 5-HT2A receptor
binding [7].
More recently, it has become possible to conduct PET imaging
of the synaptic vesicular protein 2A (SV2A) in vivo in humans and
there is some evidence to support that SV2A is an alternative
synaptic density marker to synaptophysin [45]. In a small study of
a heterogeneous group of patients with depressive symptoms,
lower presynaptic binding in terms of SV2A was found in
prefrontal cortex and hippocampus [46] and SV2A has also been
found to be upregulated in the pig brain 1 and 7 days after the pig
was given a single psychedelic dose of psilocybin [47]. There are
so far no data available from studies in humans who have taken
psychedelic drugs.
Magnetic resonance spectroscopy (MRS)
It is generally believed that extensive release of γ-aminobutyric
acid or glutamate causes dendritic spine formation [48]. 5-HT2AR
agonists such as the classical psychedelics are excitatory and
the agonist action of these substances on 5-HT2A receptors
expressed in frontal and limbic areas increases glutamatergic
transmission and thereby potentially neuroplasticity, as reviewed
in [49]. In consistency with this, a MR spectroscopy study
conducted in healthy humans under influence of psilocybin
shows that glutamate is released, at least in certain brain
regions [50] whereas in patients with MDD, glutamate is reduced
in the anterior cingulate but not in hippocampus, when
comparing pre- versus one week after psilocybin intake [23]. It
would be interesting to know if the extent to which glutamate is
released and subsequently decreased is correlated to long-lasting
psychological effects, but there are not yet data to answer that
question.
Structural MRI
Measures of structural plasticity in terms of hippocampal volume
can be assessed with structural brain MRI. As shown in a meta-
Neuropsychopharmacology (2023) 48:145 – 150
G.M. Knudsen
147
analysis of 32 MRI studies [51], MDD patients has in many, but not
all, studies been shown to have hippocampal atrophy. Moreover,
non-pharmacological treatment of depression with electroconvul-
sive therapy leads to an increase in hippocampal volume weeks
after as compared to pre-treatment volume; this is documented in
a literature review and meta-analysis of 17 studies [52, 53]. So far,
no published studies have described the long-term effects of
psychedelic therapy on hippocampal volume in patients with
MDD or in healthy controls.
Task-based functional magnetic resonance imaging (fMRI)
Whereas a number of task-based fMRI studies have investigated
the acute effects of psychedelics [54], only a few of them have
done follow-up studies or related the fMRI outcome to long-term
effects. In a longitudinal study with psilocybin, healthy volunteers
were assessed in an open-label pilot study with fMRI examinations
the day before, one week after, and one month after receiving a
25 mg/70 kg dose of psilocybin [5]. One-week post-psilocybin,
negative affect and amygdala response to facial affect stimuli
were reduced, whereas positive affect and dorsal lateral prefrontal
and medial orbitofrontal cortex responses to emotionally-
conflicting stimuli were increased. One-month post-psilocybin,
negative affective and amygdala response to facial affect stimuli
had returned to baseline levels while positive affect remained
elevated, and trait anxiety was reduced. In future studies, it will be
interesting to see if such findings not only can be replicated but
also if they represent more stable biomarkers for neuroplastic
effects.
Resting-state functional connectivity (RSFC)
Functional MR RSFC measures correlations between blood-
oxygen-level-dependent (BOLD) signals in individuals instructed
to let their mind wander [55]. Over the last years, a large range of
novel neurocomputational models have been developed and
employed to analyze datasets from patients and healthy controls
undergoing psychedelic sessions. This complicates between-
studies comparisons and, in particular, replications. Moreover, as
shown in a recent review [56], 24 out of the so far 42 published
RSFC studies have employed only two out of the 17 unique
datasets. Most of these studies involve MR-scanning in the acute
or sub-acute psychedelic phase which makes it difficult to
determine if eventual changes persist over longer periods, e.g.,
months. Only a few of the studies included follow-up data.
A single dose of psilocybin can have lasting effects on RSFC in
healthy individuals: The number of significant resting-state
functional connections across the brain increased from baseline
to 1-week and 1-month post-psilocybin [5]. There is also evidence
that RSFC is increased 24 h after intake of ayahuasca [57]. Another
study shows that one week and 3 months after a psilocybin
session, the executive control network RSFC remains decreased
compared to pre-intervention [58] and changes in brain network
integrity and segregation correlate with both plasma psilocin level
and psychedelic experience. Interestingly, the degree to which the
change in neocortex 5-HT2AR and RSFC was decreased one week
after predicted increased mindfulness 3 months later [59].
Consistent with this observation, psilocybin decreased ECN RSFC
in unmedicated, first-time MDD patients with hyper-connectivity
between the left dorsolateral prefrontal cortex and frontal and
parietal regions, nodes which commonly constitute cognitive
control networks [60]. However, a meta-analysis based on 27 seed-
based voxel-wise RSFC data sets concluded that MDD is
characterized by reduced frontoparietal control system connec-
tivity [61]. In the future, it would be valuable to investigate RSFC
longitudinally with a consensus-based methodological battery of
tools, involving larger cohorts of both MDD patients and controls
and with appropriate measures of replication. As for task-based
fMRI, it will be interesting to see if RSFC represents a more stable
biomarker for neuroplastic effects.
 G.M. Knudsen
148
VISUAL EVOKED POTENTIALS FOR MEASURING LONG-TERM
POTENTIATION (LTP)
Long-term potentiation (LTP), a form of Hebbian neuroplasticity, is
characterized by enhanced synaptic efficacy, and it is considered
the prime candidate to be the cellular correlate to experience-
dependent learning [62]. This type of synaptic plasticity is
regulated with BDNF as the primary regulator and it alters the
neuron’s structure and its functional properties. The long-term
effects of psychedelics on LTP have been electrophysiologically
documented in animal studies [28]. In humans, LTP and synaptic
plasticity can be assessed with so-called visual LTP [63] which
consists of rapid repetitive presentation of a visual checkerboard
(a photic ‘tetanus’) leads to a persistent enhancement of one of
the early components of the visual evoked potential, as measured
with electroencephalography (EEG). Also other types of sensory
stimulation which induce LTP have allowed translation from
invasive studies in animals to non-invasive human investigations
[64]. In this way, it has been shown that LTP-based neural plasticity
increases within the time frame of the antidepressant effects of
ketamine in humans, supporting the hypothesis that changes to
neural plasticity may be key to the antidepressant properties of
ketamine [65]. No studies have so far investigated the effects of
classical psychedelics on visual LTP.
SUMMARY AND SUGGESTED FUTURE RESEARCH
As should be clear from the present review, there are substantial
knowledge gaps to cover before one can confidently establish the
mechanistic relationship between exposure to single doses of
classical psychedelic drugs and long-term beneficial/therapeutic
effects in both healthy humans and in patients with psychiatric
disorders. It should also be noted that neuroplasticity per se may
not always be beneficial.
Firstly, there is a need for large-scale, placebo-controlled
randomized trials of personality, cognition, and other long-term
effects with several assessments over at least 12 months. The
studies should include a careful evaluation of the qualitative
aspects of the psychedelic experience and plasma drug levels
should be monitored throughout the session, to ensure inter-
individual comparability. In such studies, it should be verified if
serum peripheral BDNF (and potentially other neurotrophic
factors) are increased after psychedelic drug doses. Further, the
relationship between the temporal profile of serum BDNF within
the first week of exposure and long-term effects should be
analyzed. Likewise, the temporal and regional profile of brain
glutamate release, changes in brain volume, perturbations in task-
related fMRI and in RSFC would benefit from being scrutinized in
relation to short- and long-acting classical psychedelics. Common
to many of the points raised above is that knowledge about the
temporal profile of the different measures can generate a more
complete picture of what it takes to induce effects lasting for
months, or more. This can generate testable hypotheses about the
mechanisms, e.g., neuroplastic changes, behind the effects. Is
there for example a time window of a minimum duration where it
is critical that certain phenomena take place (e.g., increase in
BDNF, mystical experience, RSFC dissolution, cerebral 5-HT2AR
reduction, etc.)? And along that line, will short-acting classical
psychedelics, e.g., intravenous psilocin work as well as long-acting,
e.g., peroral LSD?
Whereas the correlation between plasma drug, cerebral
5-HT2AR occupancy, and the perceived intensity of the psyche-
delic experience is well-established for psilocybin, these associa-
tions should also be established for LSD and DMT. This would
ensure that different psychedelic drugs are compared at the same
level of 5-HT2AR occupancy, something that would also be of
importance for animal studies. Such studies could also help to
clarify if different psychedelics have the same effect at comparable
occupancy, as agonists may have different efficacy or different
functional selectivity [3, 4]. It will also be interesting to see if a
proxy for synaptic density, SV2A (as measured with PET), increases
in response to classical psychedelics. Another promising technol-
ogy that lends itself to investigations of neuroplastic effects in
humans is visual LTP.
The interindividual variability in response to psychedelic drugs,
both in terms of qualitative aspects of the experience (e.g.,
mystical experience) as well as pre-existing traits, such as
Openness, is intriguing and it needs to be established if these
traits contribute to drug expectations or through some other
mechanism, if at all. The relation between interindividual response
and cerebral 5-HT2AR density is also important to clarify.
In conclusion, there are multiple research questions to answer
before the exciting observations about neuroplastic changes that
take place in animals also are at play for the beneficial and
therapeutic effects in humans.
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ACKNOWLEDGEMENTS
NeuroPharm is a center supported by the Innovation Fund Denmark (GrantID: 4108-
00004B) and BrainDrugs by the Lundbeck Foundation (Grant ID: R279-2018-1145).
 G.M. Knudsen
150
FUNDING
GMK has received honoraria as speaker for Sage Biogen and as consultant for Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims
Sanos. NeuroPharm is a center supported by the Innovation Fund Denmark (GrantID: in published maps and institutional affiliations.
4108-00004B) and BrainDrugs by the Lundbeck Foundation (Grant ID: R279-2018-
1145).

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